The overall objective of this research plan has been to define the mechanisms responsible for repair and regeneration of alcohol-injured livers. After demonstrating that chronic consumption of alcohol inhibited proliferation of mature hepatocytes, we began to investigate whether liver progenitors were responsible for regenerating livers with alcohol-induced damage. During the last funding period we discovered that the Hedgehog (Hh) pathway regulates the fate of adult liver progenitors, and showed that this pathway is dramatically induced during alcoholic liver disease (ALD). Although Hh signaling was known to play critical roles in embryonic tissue construction, certain types of adult tissue remodeling, and tumor metastasis, it had not been implicated in adult liver repair until our work. Further efforts focused on delineating the pathobiological relevance of Hh pathway activation during ALD. We proved that Hh pathway activation causes liver epithelial progenitors to undergo epithelial-to-mesenchymal transition (EMT) and demonstrated that mice with an overly-active Hh pathway develop excessive liver fibrosis when their livers are injured. Our most recent preliminary data identify a novel mechanism for Hh pathway inhibition by demonstrating that Tweak/Fn14 signaling (which is known to promote expansion of epithelial-type liver progenitors) antagonizes the EMT-promoting actions of the Hh pathway and permits mesenchymal-to-epithelial transition (MET) in progenitors. Therefore, this competing renewal application will evaluate the HYPOTHESIS that the Hh pathway and Tweak/Fn14 differentially regulate the fate of liver progenitors, and hence the outcomes of ALD. Our Specific Aims are to 1) determine if dysregulated Hh signaling increases EMT and inhibits MET to promote fibrogeneic repair of ALD, 2) determine if Tweak/Fn14 inhibit EMT and promote non-fibrogenic repair of ALD by inhibiting Hh activity, and 3) determine if treatments that improve ALD decrease EMT and enhance MET because they inhibit Hh pathway activity and/or increase Tweak/Fn14 signaling. The results will clarify the relative significance of EMT/MET, and some of the mechanisms that regulate these processes, in controlling the divergent outcomes of ALD. This, in turn, might identify novel genetic susceptibility factors for alcohol-related cirrhosis, new biomarkers for ALD progression, and novel therapeutic targets for this common liver disease. PUBLIC HEALTH RELEVANCE: The results will clarify the relative significance of EMT/MET, and some of the mechanisms that regulate these processes, in controlling the divergent outcomes of ALD. This, in turn, might identify novel genetic susceptibility factors for alcohol-related cirrhosis, new biomarkers for ALD progression, and novel therapeutic targets for this common liver disease.